Investigating the Role of Wnt Signaling in the Mechanical Maturation of Tendon

Massachusetts General Hospital, Boston MA

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Tendon injuries are one of the leading causes of disability within the United States, directly impacting patients’ quality-of-life as even basic daily activities are impaired. This impairment is exacerbated by tendon’s poor healing capabilities, typically producing a fibrotic scar with inferior biomechanical properties and increased chance of re-injury. Despite their prevalence, clinical interventions report highly variable efficacy and new clinical therapies are required. An improved understanding of the biological mechanisms underlying tendon formation and maturation would better inform the development of new clinical strategies aimed at improving tendon structure and function following injury and lead to more effective treatments for patients. Here, we focus on a critical phase in postnatal tendon maturation defined by decreased tendon cell proliferation, maturation of the matrix, and an abrupt increase in the biomechanical capabilities of the tendon. While the timing may vary, this mechanical transformation is conserved across species and is critical to the acquisition of load-bearing activities. While significant progress has been made in decoupling the underlying structural elements that mediate this process, the cellular and molecular mechanisms regulating this transformation remain unclear and may offer novel insights for the advancement of current clinical strategies. Intriguingly, our preliminary data has identified that Wnt signaling and a Wnt-responsive cellular population, marked by Axin2 expression, may play a crucial role in this key phase of postnatal tendon maturation. However, further work is required to understand their contribution to tendon fate and the underlying molecular mechanisms by which they are regulated. Therefore, the goal of this proposal is to elucidate the function(s) of Wnt signaling in postnatal tendon maturation and test if mechanical cues contribute to an Axin2-lineage cell fate and/or the regulation of Wnt signaling in the maturing tendon niche. Based on our preliminary data, we hypothesize that Wnt signaling is integral for proper tendon cell behavior, gene expression, and deposition/organization of the extracellular matrix, which ultimately define the mechanical fate of tendons, and is regulated by mechanobiological signaling activity. In Aim 1, we will define the function of Wnt signaling and identify Wnt-responsive cell populations during the establishment of this critical structure-function transformation in postnatal tendons. In Aim 2, we will investigate if Wnt is regulated by mechanobiological signaling activity during postnatal maturation and explore other molecular pathways and cell populations that are dependent upon mechanical cutes during this critical phase of tendon development. Altogether, this work will provide key insight into understanding the complex cellular population, biomolecular, and biomechanical interactions which mediate the formation of a robust tendon matrix. These principles will provide the framework for new regenerative strategies to improve human clinical treatments following tendon disease or injury.